Cytokines, a family of molecules that includes growth factors, as well as inflammatory peptides, are the soluble mediators of chondrocyte regulation and tissue repair. The interactions between the regulatory components are complex and not well-understood, but an understanding of, and the ability to manipulate chondrocyte metabolic activities, are essential to the goal of biologically-driven intrinsic repair of articular cartilage. Cartilage has been demonstrated to be a reservoir for TGF-beta1 and to display changes in chondrocyte proliferation and proteoglycan synthesis in the presence of TGF-beta1. However, what gives specificity to the physiologic response to TGF-beta1 is not clear. The major hypothesis of this proposal is that the insoluble extracellular matrix of articular cartilage provides a component of the chondrocyte regulation by modulating the actions of chondrocytes. To address the goals of this proposal, the following Specific Aims will be examined: 1) the effect of exogenous type II collagen on TGF-beta1-stimulated chondrocyte metabolism and gene expression, using isolated bovine chondrocytes in an alginate bead culture system; 2) the alteration in proteoglycan species synthesized in the presence of extracellular type II collagen; 3) the concentration dependence of TGF-beta1 on the observed modulation by type II collagen; and 4) the role of anchorin and integrins in the signaling by the extracellular collagen. It is suggested by the applicant that an understanding of the local regulation of the articular chondrocyte is a preliminary requirement to guide biologic modulation of intrinsic articular cartilage repair in orthopaedic patients with post-traumatic and osteo-arthritis. It is proposed that, only through a comprehensive approach to the regulatory milieu will we come to understand the local regulatory environment of the chondrocyte and to gain insight into stimulating an intrinsic articular repair process.